Conformation-dependent binding of a Tetrastatin peptide to αβ integrin decreases melanoma progression through FAK/PIK/Akt pathway inhibition.
Fiche publication
Date publication
juin 2018
Journal
Scientific reports
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BRASSART-PASCO Sylvie, Pr DAUCHEZ Manuel, Dr MONBOISSE Jean-Claude, Pr RAMONT Laurent, Dr BRASSART Bertrand, Dr OUDART Jean-Baptiste, Pr BAUD Stéphanie
Tous les auteurs :
Lambert E, Fuselier E, Ramont L, Brassart B, Dukic S, Oudart JB, Dupont-Deshorgue A, Sellier C, Machado C, Dauchez M, Monboisse JC, Maquart FX, Baud S, Brassart-Pasco S
Lien Pubmed
Résumé
Tetrastatin, a 230 amino acid sequence from collagen IV, was previously demonstrated to inhibit melanoma progression. In the present paper, we identified the minimal active sequence (QKISRCQVCVKYS: QS-13) that reproduced the anti-tumor effects of whole Tetrastatin in vivo and in vitro on melanoma cell proliferation, migration and invasion. We demonstrated that QS-13 binds to SK-MEL-28 melanoma cells through the αβ integrin using blocking antibody and β3 integrin subunit siRNAs strategies. Relevant QS-13 conformations were extracted from molecular dynamics simulations and their interactions with αβ integrin were analyzed by docking experiments to determine the binding areas and the QS-13 amino acids crucial for the binding. The in silico results were confirmed by in vitro experiments. Indeed, QS-13 binding to SK-MEL-28 was dependent on the presence of a disulfide-bound as shown by mass spectroscopy and the binding site on αβ was located in close vicinity to the RGD binding site. QS-13 binding inhibits the FAK/PIK/Akt pathway, a transduction pathway that is largely involved in tumor cell proliferation and migration. Taken together, our results demonstrate that the QS-13 peptide binds αβ integrin in a conformation-dependent manner and is a potent antitumor agent that could target cancer cells through αβ.
Référence
Sci Rep. 2018 Jun 29;8(1):9837